Project Summary The overall goal of the proposed research is to determine the relationship between remote ischemic preconditioning (RIPC) and a novel exercise modality called ?occlusive exercise?. Findings from this investigation will have direct relevance to the exercise component of stroke rehabilitation. Stroke is one of the leading causes of potentially preventable death and disability worldwide and extensive research has been focused on developing therapies for its treatment and prevention. One such therapy is a technique known as remote ischemic preconditioning (RIPC). This technique is characterized by restricting blood flow to an arm or leg for a short period of time (e.g., 5 min) then rapidly releasing the occlusive stimulus. RIPC has demonstrated its efficacy in numerous clinical settings, and the protection it confers is now known to be mediated by the release of various factors into the circulation. These factors include catecholamines, nitrate, cytokines, endogenous opioids, and others. Our central hypothesis is that a novel exercise modality called ?occlusive exercise? will elicit similar cerebro-protective effects as RIPC via the release of the same circulating mediators. This form of training, which is characterized by restricting blood flow to the active muscles, is already undergoing trials in some clinical populations. Specific aim 1 will compare the release of the protective factors known to be associated with RIPC between an acute bout of traditional exercise, occlusive exercise, and RIPC. We hypothesize that combining exercise with RIPC in the form of occlusive exercise will result in an even greater release of these factors than either exercise or RIPC alone. One concern that has been raised about the utilization of occlusive exercise in a rehabilitative setting is the potential for an augmentation of the exercise pressor reflex, which could cause an unsafe rise in arterial pressures. To address this concern, Specific aim 2 will comprehensively compare the hemodynamic and cerebrovascular responses between traditional exercise, occlusive exercise, and RIPC. We hypothesize that the exercise-induced elevation in arterial blood pressure, heart rate (HR), and cerebral blood flow will be attenuated with occlusive exercise, due to the use of lower workloads. The rationale for the proposed research is to extend the application of RIPC beyond the pre-operative setting to which it is currently limited. While we cannot anticipate when a stroke will occur, we can target our therapies to high-risk populations. One such population is stroke survivors, as a significant portion of these individuals will suffer from a recurrent stroke. Many of these patients are already participating in exercise as part of their rehabilitation; thus, if the same factors known to be released with RIPC are also released with occlusive exercise, then this rehabilitation would be the ideal environment to incorporate this novel training modality. This project is innovative in that it expands the reach of RIPC beyond the operating room, into a population pool that could likely benefit from its application. This investigation will fill the gap in our knowledge regarding the possibility that the cerebro-protective effects of RIPC can be emulated by occlusive exercise.